Intramuscular injection forms of gyrase inhibitors

ABSTRACT

Ciprofloxacin and related gyrase inhibitors are tolerated well if administered intramuscularly in the form of an aqueous suspension of the betaine form having an approximate neutral pH value or in the form of an oily suspension of the betaine or salts thereof. Oily suspensions which contain the active material in water-soluble form, eventually in form of the hydrochlorides, lactates, mesilates, methanesulfonates and other salts, are capable of releasing the active compound very rapidly, particularly when the wettability of the oily carrier medium is increased by addition of interfacially surface active materials.

This application is a continuation, of application Ser. No. 334,252,filed Apr. 6, 1989.

The invention relates to intramuscular injection forms which contain, asthe active compound, gyrase inhibitors from the group comprisingquinolone- and 1,8-naphthyridone-3-carboxylic acids, their preparationand their use as medicaments.

Tablets for peroral administration and relatively large volume infusionsolutions (0.2% strength/50, 100 ml) and infusion concentrates (1%strength/10 ml) containing, for example, ciprofloxacin as the activesubstance have so far been available. In contrast, no satisfactoryformulation has to date been developed for intramuscular administration.Solutions of, for example, ciprofloxacin of up to 5% strength forintramuscular administration are thus very poorly tolerated because oftheir non-physiological pH in the acid or alkaline range. Afterintramuscular injection of aqueous acid or alkaline solutions,considerable intolerances and damage up to necroses have been found inthe muscular tissue.

Surprisingly, it has now been found that ciprofloxacin is tolerated wellfollowing intramuscular administration if it is administered in the formof an aqueous suspension of the betaine form having an approximateneutral pH value or in the form of an oily suspension of the betaine orsalts thereof. Moreover it has been found surprisingly that oilysuspensions which contain ciprofloxacin in water-soluble form,eventually in form of the hydrochlorides, lactates, mesilates,methanesulfonates and other salts, are capable of releasing the activecompound very rapidly, particularly when the wettability of the oilycarrier medium is increased by addition of interfacially surface activematerials. To the contrary aqueous suspensions which contain the activecompound in the form of betaine ensure protracted release of the activecompound.

Regulation and control of release of the active compound is possible viachoice of particle size and the combination of auxiliaries respectively.

The invention relates to intramuscular injection formulations of gyraseinhibitors containing 0.05 to 70% by weight of a gyrase inhibitor of thegeneral formula ##STR1## in which R¹ stands for methyl, ethyl, propyl,isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy,amino, methylamino, dimethylamino, ethylamino, phenyl, 4-fluorophenyl or2,4-difluorophenyl,

R² stands for hydrogen, alkyl having 1 to 4 carbon atoms or(5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl,

R³ stands for methyl or a cyclic amino group, such as ##STR2## whereinR⁴ stands for hydrogen, alkyl having 1 to 4 carbon atoms,2-hydroxyethyl, allyl, propargyl, 2-oxopropyl, 3-oxobutyl, phenacyl,formyl, CFCl₂ -S-, CFCl₂ -SO₂ -, CH₃ O-CO-S-, benzyl, 4-aminobenzyl or##STR3## R⁵ stands for hydrogen or methyl, R⁶ stands for hydrogen, alkylhaving 1 to 4 carbon atoms, phenyl or benzyloxymethyl,

R⁷ stands for hydrogen, amino, methylamino, ethylamino, aminomethyl,methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, hydroxyl orhydroxymethyl and

R⁸ stands for hydrogen, methyl, ethyl or chlorine,

X stands for fluorine, chlorine or nitro and

A stands for N or C-R⁶,

wherein

R⁶ stands for hydrogen, halogen, such as fluorine or chlorine, methyl ornitro or, together with

R¹, can also form a bridge having the structure ##STR4## if appropriateas a salt with an acid or base or as a pro-drug, in aqueous or oilysuspension.

Not only a systemic action, which can be controlled with respect totime, depending on the composition of the formulation, can be achievedwith the intramuscular injections containing gyrase inhibitors. Inaddition, local infection foci can also be reached by the direct routeand treated in a targeted manner over relatively long periods of time.

The gyrase inhibitors can be used in the aqueous and oily injectionforms as such or as a salt with an acid or base. It is also possible touse them as a prodrug, for example in the form of esters.

The formulations according to the invention contain 0.05-70% by weight,preferably 2.5-50% by weight, of the active compound.

The suspensions according to the invention for intramuscular injectionparticularly preferably contain 10-60% weight/weight of the activecompound of the above formula.

The formulations mentioned contain, in particular, ciprofloxacin,norfloxacin, pefloxacin, amifloxacin, pirfloxacin, ofloxacin,fleroxacin, lomefloxacin and/or enoxacin. The formulations according tothe invention especially preferably also contain the active compounds ofEuropean Patent Applications 153,163, 106,489, 153,828, 195,316, 167,763and 126,355.

The following active compounds may be mentioned in particular:6-chloro-7-[3-(4-chlorophenyl)-1-piperazinyl]-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,6-chloro-1-cyclopropyl-8-fluoro-7-[3-(4-fluorophenyl)-1-piperazinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,7-[3-(4-bromophenyl)-1-piperazinyl]-6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7-[3-(4-methylphenyl)-1-piperazinyl]-4-oxo-3-quinolinecarboxylicacid,7-[3-(4-biphenylyl)-1-piperazinyl]-6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7-[3-(4-methoxyphenyl)-1-piperazinyl]-4-oxo-3-quinolinecarboxylicacid,6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7-[3-(4-hydroxyphenyl)-1-piperazinyl]-4-oxo-3-quinolinecarboxylicacid,8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-phenyl-1-piperazinyl)-3-quinolinecarboxylicacid, 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[(4-nitrophenyl)-1-piperazinyl]-3-quinolinecarboxylicacid,8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-(4-piperidinophenyl)-1-piperazinyl]-3-quinolinecarboxylicacid,8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8-[3-(3,4-dimethoxyphenyl)-1-piperazinyl]-3-quinolinecarboxylicacid,8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-(3,4,5-trimethoxyphenyl)-1-piperazinyl]-3-quinolinecarboxylicacid,8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-(2-thienyl)-1-piperazinyl]-3-quinolinecarboxylic acid,8-chloro-1-cyclopropyl,6-fluoro-1,4-dihydro-4-oxo-7-piperidino-3-quinolinecarboxylicacid,7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (active compound B),6,8-dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylicacid,7-(4-acetyl-1-piperazinyl)-6,8-dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,7-(4-acetyl-1-piperazinyl)-6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7-(4-isopropyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylicacid,6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-7-morpholino-3-quinolinecarboxylicacid,6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-7-thiomorpholino-3-quinolinecarboxylicacid,8-chloro-1-cyclopropyl-7-(4-ethyl-3-oxo-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylicacid, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)-3-quinolinecarboxylic acid,1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-ethyl-1-piperazinyl)-3-quinolinecarboxylicacid,1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-methyl-1-piperazinyl)-3-quinolinecarboxylicacid,1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3,4-dimethyl-1-piperazinyl)-3-quinolinecarboxylicacid,1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-ethyl-3-methyl-1-piperazinyl)-3-quinolinecarboxylicacid,1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-[4-(2-hydroxyethyl)-3-methyl-1-piperazinyl]-3-quinolinecarboxylicacid,1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-[4-(3-hydroxypropyl)-3-methyl-1-piperazinyl]-3-quinolinecarboxylicacid,1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(2,5-dimethyl-1-piperazinyl)-3-quinolinecarboxylicacid,1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-ethyl-2,5-dimethyl-1-piperazinyl)-3-quinolinecarboxylicacid,1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3,5-dimethyl-1-piperazinyl)-3-quinolinecarboxylicacid (active compound A),1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3,4,5-trimethyl-1-piperazinyl)-3-quinolinecarboxylicacid,1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-ethyl-3,5-dimethyl-1-piperazinyl)-3-quinolinecarboxylicacid,1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-ethyl-1-piperazinyl)-3-quinolinecarboxylicacid,1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-n-propyl-1-piperazinyl)-3-quinolinecarboxylicacid,1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-aminopyrrolidinyl)-3-quinolinecarboxylicacid (active compound C),1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-isopropyl-1-piperazinyl)-3-quinolinecarboxylicacid,1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-isobutyl-1-pipereazinyl)-3-quinolinecarboxylicacid,1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-(3-methyl-4-n-propyl-1-piperazinyl)-3-quinolinecarboxylicacid,1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-methyl-4-isopropyl)-1-piperazinyl)-3-quinolinecarboxylicacid, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-n-butyl-3-methyl-1-piperazinyl)-3-quinolinecarboxylic acid and1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-morpholinyl-3-quinolinecarboxylicacid, and their pharmaceutically usable acid addition salts, alkalimetal salts, alkaline earth metal salts or hydrates.

Finally, ciprofloxacin or enrofloxacin are also particularly preferablyemployed as the active compound in the formulations according to theinvention.

In addition to water for injection purposes, aqueous suspensions forintramuscular injection can furthermore also contain as the liquidexcipient, for example, ethanol, glycerol, propylene glycol,polyethylene glycol and triethylene glycol. Various substances such asphosphate, citrate, tris, ascorbate, acetate, succinate, tartrate,gluconate and lactate buffers can be used for adjusting the pH as far aspossible to within the physiological range of about pH 7.4 or forbuffering. The pH of the aqueous formulations according to the inventionis 4.5-8.5, preferably 6.5-7.5. The osmolality of the aqueoussuspensions is 200-900 m osmol/kg, preferably 260-390 m osmol/kg, andcan be adjusted to suit isotonic conditions by additions of NaCl,glucose, fructose, glycerol, sorbitol, mannitol, sucrose or xylitol ormixtures of these substances.

It is moreover possible to use other formulating agents, such asthickeners (for example methylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, sodium carboxymethylcellulose,polyvinylpyrrolidone, gelatine and the like), absorption agents, lightscreens, absorption inhibitors, crystallization retarders, complexingagents (for example NaEDTA, phosphates, nitrates, acetates, citrates andothers), antioxidants (ascorbic acid, sulphite compounds, L-cysteine,thiodipropionic acid, thiolactic acid, monothioglycerol, propyl gallateand others) and preservatives (PHB esters, phenol and derivatives,organomercury compounds, chlorobutanol, benzyl alcohol, ethanol,1,3-butanediol, benzalkonium chloride, chlorhexidine salts, benzoic acidand salts, sorbic acid and others). Local anaesthetics, such as, forexample, procaine HCl, lidocaine HCl and others, can be added to theaqueous suspensions if appropriate.

When preparing the aqueous suspensions, it must be ensured that theparticle size is 0.5-50 μm, in particular 4-40 μm. Control of therelease of active compound from the intramuscular suspension depot canbe achieved by controlled mixing of different particle size classes ofthe active substance.

In the case of aqueous suspensions, the particle sizes of 90% of theparticles are preferably 10-20 μm. The viscosity of the aqueoussuspensions is 5-500 mPa.s, preferably 10-130 mPa.s.

Aqueous suspensions of gyrase inhibitors can be prepared in variousways. On the one hand, the active compounds from the gyrase inhibitorclass can be incorporated in micronized form into the aqueous excipientmedium, the auxiliaries mentioned being included; in this procedure, itshould strictly be ensured that no crystal growth occurs beyond thelimits mentioned. If appropriate, the active compound must be preparedin the form of one of its stable hydrate stages and further processed toa suspension. If final sterilization by heat is not possible,manufacture must be carried out under aseptic conditions usingpretreated active compounds and auxiliaries. Final sterilization, as byradiation is possible.

Aqueous suspensions of gyrase inhibitors of the quinolone type canmoreover be prepared by controlled precipitation from a solution; thereis the possibility, for example, of dissolving the active compound in aphysiologically tolerated acid from the group consisting of hydrochloricacid, methanesulphonic acid, propionic acid, succinic acid, glutaricacid, citric acid, fumaric acid, maleic acid, tartaric acid, glutamicacid, gluconic acid, glucuronic acid, galacturonic acid, ascorbic acid,phosphoric acid, adipic acid, hydroxyacetic acid, sulphuric acid, nitricacid, acetic acid, malic acid, L-aspartic acid, lactic acid, isethionicacid, lactobionic acid and oxatic acid or in amino acids from the groupconsisting of L-Arginine, L-Aspartic, L-Cysteic, L-Glutamic, Glycine,L-Leucine, L-Lysine and L-Serine, if appropriate while warming slightly,preferably to 20°-80° C.

An excess of acid is preferably used, for example in accordance with thedoctrine of European Patent Applications 86 114 131.5 and 84 110 474.8.The acid solution is then adjusted to the physiological pH of 7 byaddition of a physiologically tolerated alkaline solution, for exampleof sodium hydroxide, potassium hydroxide or meglumine, the activecompound being precipitated out of the solution in finely divided form.On the other hand, there is also the possibility of dissolving theactive compound of the quinolone/naphthyridone gyrase inhibitor type inan alkaline medium using one of the bases mentioned and then toprecipitate it by one of the acids mentioned.

However, the acids and alkaline solutions can be combined without usingpressure, but also with pressure, in a range from 2 to 100 bar, it beingpossible to control the resulting particle size in the suspension viathe preparation conditions defined. The actual precipitation operationcan also be followed by additional homogenization using high-speedstirrers, rotor-stator homogenizers, high pressure homogenizers(100-1000 bar) and similar methods. If final sterilization is prohibitedbecause of possible particle growth, the suspension is to be preparedunder aseptic conditions by combining sterilized and sterile-filteredacid and basic part components with one another under strictly asepticconditions. If appropriate, one of the preservatives mentioned or acombination thereof can be employed in a suitable dosage in order toguarantee a germ-free preparation. Final sterilization in form of aγ-ray sterilization may be applied too.

A presentation form which contains the active compound in a dry formwithout a liquid excipient can moreover be provided. The separate liquidexcipient is combined with the solids content of the recipe only shortlybefore administration, in which case homogeneous distribution of thesolids particles in the liquid phase must be guaranteed by briefshaking.

Under the provisions set forth hereinabove and hereinbelow there areparticularly preferred oil based intramuscular injection formulationswhich contain the active compound in water-soluble, crystalline oramorphous form, for instance in form of the hydrochloride, lactate,mesilate, p-tolyl sulphonate or other salts produced withphysiologically well-tolerated acids as well as which containinterfacially active substances, as for instance lecithin in the form ofsoy bean lecithin, egg lecithin, brain lecithin or rape lecithin orother physiologically well-tolerated tensides in concentrations of 0.1to 30%, particularly 0.2 to 10%, above all 0.5 to 5.0% W/V as well aswhich contain, in addition to the water-soluble active compound in theform of their salts, an excess of physiologically well-tolerated acids,as for instance lactic acid or citric acid in the range of 1 to 300mmol/1, particularly 5 to 50 mmol/1, preferably 10 to 30 mmol/1.

Oily suspensions of quinolone-type gyrase inhibitors contain the activecompound either in the form of the betaine or in the form ofwater-soluble salts. Physiologically well-tolerated acids appropriatefor formation of salts are set forth hereinabove.

Oily suspensions can contain, as non-aqueous excipients, for examplealmond oil, arachis oil, olive oil, poppyseed oil, sesame oil,cottonseed oil, soya bean oil, corn oil, castor oil, ethyl oleate, oleyloleate, isopropyl myristate, isopropyl palmitate, medium-chaintriglycerides and others. Ethanol, glycerol, propylene glycol,polyethylene gLycoL, 1.3-butane diol, benzyl alcohol, diethylene glycoland triethylene glycol of various origins,polyoxyethylene-polyoxypropylene copolymers of the Pluronic® type,polyoxysorbitan fatty acid esters, sorbitan fatty acid esters monoolein,cremophor EL®, Inwitor 742® and different types of lecithin such as soybean lecithin, egg lecithin, brain lecithin and rape lecithin can beused as further auxiliaries which can be combined with the substancesmentioned.

Antioxidants which are used are α-, β-, γ- and δ-tocopherol, ascorbylpalmitate, ascorbyl stearate, L-cysteine, thiodipropionic acid,thiolactic acid, thioglycolic acid, monothioglycerol, propyl gallate,butylhydroxyanisole, butylhydroxytoluene and others.

If appropriate, a desired viscosity can be brought about by diluentssuch as ethanol or benzyl alcohol and by thickeners such as aluminumstearate. Acids such as those mentioned hereinabove may be added asabsorption enhancers. Viscosity values for oily suspensions are 5-500mPa.s, preferably 10-150 mPa.s.

Oily suspensions are prepared by combining the oily excipient with theauxiliaries contained therein and the active compound, which has beencomminuted to the desired particle size, using suitable apparatuses (seeabove) and homogenizing the mixture. The particle sizes of 90% of theparticles are 0.5-150 μm, preferably 4-12 μm. If final sterilization inthe release vessel is prohibited because of a possible change in theparticle size of the active compound, the suspension must again beprepared under aseptic conditions. Sterile filtration of the oily phasecontaining suitable auxiliaries in dissolved form is also indicated,such as antimicrobial pretreatment of the active compound, for exampleby heat treatment. Final sterilization in the form of a γ-raysterilization may also be applied.

In addition to a finished suspension, a formulation which is to befreshly prepared shortly before administration can also be provided. Inthis case, the active compound must be homogeneously suspendable in theliquid excipient within a short time by shaking the vessel containingthe formulation.

The invention also relates to suspension concentrates which areconverted into the formulations according to the invention shortlybefore administration.

These concentrates can have various compositions. This invention relatesto all the further combinations of concentrates and/or suspensions andsolvents or solutions required for dilution which lead to thesuspensions according to the invention.

This invention also relates to other presentation forms or combinationsof presentation forms which in the end lead to the injection solutionsaccording to the invention--regardless of the procedure.

The containers filled with suspensions, active compound, solvents andother presentation forms, such as suspension concentrates, can be madeof glass or of plastic. The container materials here can containsubstances which impart special protection to the contents, such as, forexample, protection from light or protection from oxygen. In addition tosmall volume vessels, from which the suspension must be drawn into theinjection syringe before administration, the vessels here can also befinished injection systems.

The injection formulations according to the invention are used in thetherapeutic treatment of the human or animal body.

The formulations according to the invention have a low toxicity andexhibit a broad antibacterial spectrum against Gram-positive andGram-negative germs, in particular against Enterobacteriaceae; above allalso against those which are resistant towards various antibiotics, suchas, for example, penicillins, cephalosporins, aminoglycosides,sulphonamides and tetracyclines.

The formulations according to the invention are active against a verybroad spectrum of microorganisms. Gram-negative and Gram-positivebacteria and bacteria-like microorganisms can be combated and thediseases caused by these pathogens can be prevented, alleviated and/orcured with the aid of these formulations.

The formulations according to the invention are particularly activeagainst bacteria and bacteria-like microorganisms. They are thereforeparticularly suitable for the prophylaxis and chemotherapy, in human andveterinary medicine, of local and systemic infections caused by thesepathogens.

For example, it is possible to treat and/or prevent local and/orsystemic diseases caused by the following pathogens or by mixtures ofthe following pathogens: Gram-positive cocci, for example Staphylococci(Staph. aureus and Staph. epidermidis) and Streptococci (Strept.agalactiae, Strept. faecalis, Strept. pneumoniae and Strept. pyogenes);Gram-negative cocci (Neisseria gonorrhoeae) and Gram-negative rod-shapedbacilli, such as Enterobacteriaceae, for example Escherichia coli,Haemophilus influenzae, Citrobacter (Citrob. freundii and Citrob.divernis), Salmonella and Shigella; and furthermore Klebsiellae (Klebs.pneumoniae, Klebs. oxytoca), Enterobacter (Ent. aerogenes and Ent.agglomerans), Hafnia, Serratia (Serr. marcescens), Proteus (Pr.mirabilis, Pr. rettgeri and Pr. vulgaris), Providencia and Yersinia, andthe genus Acinetobacter. The antibacterial spectrum moreover includesthe genus Pseudomonas (Ps. aeruginosa and Ps. maltophilia) and strictlyanaerobic bacteria, such as, for example, Bacteroides fragilis,representatives of the genus Peptococcus and Peptostreptococcus and thegenus Clostridium; and furthermore Mykoplasma (M. pneumoniae, M. hominisand M. urealyticum) and Mycobacteria, for example Mycobacteriumtuberculosis.

The above list of pathogens is to be interpreted merely by way ofexample and in no way as limiting. Examples which may be mentioned ofdiseases which can be caused by the pathogens or mixed infectionsmentioned and can be prevented, alleviated or cured by the compoundsaccording to the invention are: infection diseases in humans, such as,for example, otitis, pharyngitis, pneumonia, peritonitis,pyelonephritis, cystitis, endocarditis, systemic infections, bronchitis(acute and chronic), septic infections, diseases of the upperrespiratory tract, diffuse panbronchiolitis, pulmonary emphysema,dysentery, enteritis, liver abscesses, urethritis, prostatitis,epididymitis, gastrointestinal infections, bone and joint infections,cystic fibrosis, skin infections, postoperative wound infections,abscesses, phlegmons, wound infections, infected burns, burn wounds,infections in the oral region, infections following dental operations,osteomyelitis, septic arthritis, cholecystitis, peritonitis withappendicitis, cholangitis, intraabdominal abscesses, pancreatitis,sinusitis, mastoiditis, mastitis, tonsillitis, typhoid, meningitis andinfections of the nervous system, salpingitis, endometritis, genitalinfections, pelveoperitonitis and eye infections.

Bacterial infections can also be treated in other species as well as inhumans. Examples which may be mentioned are:

pigs: colidiarrhoea, enterotoxaemia, sepsis, dysentery, salmonellosis,mastitis-metritis agalactia syndrome and mastitis;

ruminants (cattle, sheep, goats): diarrhoea, sepsis, bronchopneumonia,salmonellosis, pasteurellosis, mycoplasmosis and genital infections;

horses: bronchopneumonia, joint ill, puerperal and postpuerperalinfections and salmonellosis;

dogs and cats: bronchopneumonia, diarrhoea, dermatitis, otitis, urinarytract infections and prostatitis; poultry (chickens, turkeys, quails,pigeons, ornamental birds and others): mycoplasmosis, E. coliinfections, chronic diseases of the respiratory tract, salmonellosis,pasteurellosis and psittacosis.

Bacterial diseases can also be treated in the rearing and keeping ofstock and ornamental fish, the antibacterial spectrum extending beyondthe abovementioned pathogens to further pathogens, such as, for example,Pasteurella, Brucella, Campylobacter, Listeria, Erysipelothrix,Corynebacteria, Borrelia, Treponema, Nocardia, Rickettsia and Yersinia.

The auxiliaries mentioned in the examples are commercially available andare defined in part in H. P. Fiedler, Lexikon der Hilfsstoffe furPharmazie, Kosmetik und angrenzende Gebiete (Dictionary of Auxiliariesfor Pharmacy, Cosmetics and Related Areas), Editio Cantor KG - Aulendorfi. Wurtt. 1971 (for example Tween® and Miglyol®).

The invention will be further described with reference to theaccompanying drawings relating to comparison experiments whichdemonstrate the good tolerability of a ciprofloxacin intramuscularsuspension in contrast to ciprofloxacin intramuscular solutions.

FIG. 1 shows the course of the creatinine kinase following intramuscularadministration of ciprofloxacin intramuscular solutions, anintramuscular suspension and comparison solutions.

FIG. 2 shows the local irritation following intramuscular administrationof ciprofloxacin solutions and a ciprofloxacin intramuscular suspensionand comparison solutions.

FIG. 3 shows the blood plasma levels after application of an oilyciprofloxacin-HCl suspension to rabbits.

The very fast absorption of Ciprofloxacin-HCl from an oily suspensioninto the blood is clearly evident.

Results

1) The local irritations following intramuscular administration of 5%weight/volume ciprofloxacin suspensions are clearly less than thosecaused by intramuscular solutions (Rabbit test)

2) In contrast to the intramuscular solutions tested, administration ofthe ciprofloxacin suspension causes no increase in the serum creatininekinase.

The formulations used for the experiments are described below (rabbittest).

    ______________________________________                                        Ciprofloxacin intramuscular injection solution                                5% w/v                                                                        Ciprofloxacin         50.0       g                                            Lactic acid saponified 20%                                                                          131.0      g                                            Water for injection purposes                                                                        840.6      g                                                                  1021.6     g                                            clear yellowish solution; pH 3.9, isotonic                                    Ciprofloxacin intramuscular injection solution                                5% weight/volume 2 ml                                                         B                                                                             Ciprofloxacin         50.0       g                                            100% strength acetic acid                                                                           25.0       g                                            Water for injection purposes                                                                        943.7      g                                                                  1,018.7    g (1 l)                                      clear, yellow solution; pH 4.2                                                Ciprofloxacin intramuscular injection solution                                5% weight/volume 2 ml                                                         C                                                                             Ciprofloxacin         50.0       g                                            Methanesulphonic acid 14.5       g                                            Anhydrous glycerol    12.5       g                                            0.1 N NaOH solution   to pH 4.2                                               Water for injection purposes                                                                        945.5      g                                                                  1,022.5    g (1 l)                                      Clear, yellow solution; pH 4.2                                                Ciprofloxacin intramuscular suspension                                        5% weight/volume 2 ml                                                         D                                                                             Ciprofloxacin         50.0       g                                            20% weight/weight NaOH solution                                                                     55.2       g                                            Citric acid fine grit 17.9       g                                            Tylopur C 300 P       2.0        g                                            Water for injection purposes                                                                        907.3      g                                                                  1,032.4    g (1 1)                                      Sedimenting, reshakable suspensions of pH 7; particle                         size of the crystals predominantly less than 10 μm.                        Ciprofloxacin suspension 5% w/v                                                E                                                                            Ciprofloxacin-HCl     58.2       g                                            Phospholipon 100      5.0        g                                            Benzyl alcohol distilled                                                                            20.0       g                                            Miglyol 812 ®     883.8      g                                                                  967.0      g                                            white oily suspension;                                                        Ciprofloxacin placebo                                                         F                                                                             Lactic acid saponified 20%                                                                          64.06      g                                            2 N NaOH - solution   38.4       g                                            Sodium chloride       1.46       g                                            Water for injection purposes                                                                        900.08     g                                                                  1004.0     g                                            clear colorless solution isotonic; pH 3.9                                     Ciprofloxacin placebo                                                         Ciprofloxacin intramuscular injection solution placebo                        5% weight/volume 2 ml                                                         G                                                                             100% strength acetic acid                                                                           50.0       g                                            1 N NaOH solution     to pH 4.2                                               Water for injection purposes                                                                        956.7      g                                                                  1,006.7    g                                            Clear, colorless solution; pH about 4.2                                       Ciprofloxacin placebo                                                         Ciprofloxacin intramuscular injection solution placebo                        5% weight/volume 2 ml                                                         H                                                                             Methanesulphonic acid 14.5       g                                            Anhydrous glycerol    12.5       g                                            1 N NaOH solution     about 158.06                                                                             g                                            Water for injection purposes                                                                        825.54     g                                                                  1,010.6    g                                            Clear, almost colorless solution;                                             pH about 4.2                                                                  Osmolality about 425 m osmol                                                  Ciprofloxacin placebo                                                         Ciprofloxacin intramuscular injection solution placebo                        5% weight/volume 2 ml                                                         J                                                                             Citric acid fine grit 17.9       g                                            20% weight/weight NaOH solution                                                                     55.6       g                                            Tylopur C 300 P ® 2.0        g                                            Water for injection purposes                                                                        940.3      g                                                                  1,015.8    g (1 l)                                      Colorless, slightly opalescent solution; pH 6.8                               ______________________________________                                        Examples                                                                      ______________________________________                                        Ciprofloxacin     50       g     preparation by                               20% weight/weight NaOH                                                                          55.2     g     precipitation                                solution                                                                      Citric acid       17.9     g                                                  Tylopur C 300 P ®                                                                           --                                                          Water             909.3    g     pH = 6.5                                     Ciprofloxacin     50       g     preparation by                               20% weight/weight NaOH                                                                          55.2     g     precipitation                                solution                                                                      Citric acid       17.9     g                                                  Tylopur C 300 P ®                                                                           2.0      g                                                  Water             907.3    g     pH = 6.7                                     Ciprofloxacin     50       g     preparation by                               20% weight/weight NaOH                                                                          55.2     g     precipitation                                solution                                                                      Citric acid       17.9     g                                                  Tylopur C 300 P ®                                                                           5.0      g                                                  Water             904.3    g     pH = 6.5                                     Ciprofloxacin     50       g     preparation by                               20% weight/weight NaOH                                                                          55.2     g     precipitation                                solution                                                                      Citric acid       17.9     g                                                  Tylopur C 300 P ®                                                                           7.5      g                                                  Water             901.8    g     pH = 6.5                                     Ciprofloxacin     50       g     preparation by                               20% weight/weight NaOH                                                                          55.2     g     precipitation                                solution                                                                      Citric acid       17.9     g                                                  Tylopur C 300 P ®                                                                           7.5      g                                                  Water             899.5    g     pH = 6.5                                     Ciprofloxacin     50       g     preparation by                               20% weight/weight NaOH                                                                          55.2     g     precipitation                                solution                                                                      Citric acid       16.0     g                                                  Tylopur C 300 P ®                                                                           2.0      g                                                  Water             909.2    g     pH = 7.9                                     Ciprofloxacin     50       g     preparation by                               20% weight/weight NaOH                                                                          55.2     g     precipitation                                solution                                                                      Citric acid       24.7     g                                                  Tylopur C 300 P ®                                                                           2.0      g                                                  Water             900.5    g     pH = 5.3                                     Ciprofloxacin     50       g     preparation by                               20% weight/weight NaOH                                                                          55.2     g     precipitation                                solution                                                                      Citric acid       17.9     g                                                  Tylopur C 300 P ®                                                                           2.0      g                                                  Tween 20          2.0      g                                                  Water             900.5    g     pH = 6.9                                     Ciprofloxacin     5.0      g     preparation by                               20% weight/weight NaOH                                                                          9.43     g     precipitation                                solution                                                                      Lipoid E 80       0.2      g                                                  Citric acid       1.8      g                                                  Tylopur C 300 P ®                                                                           0.2      g                                                  Water             77.17    g                                                  10.                                                                           Ciprofloxacin     50.0     g     preparation by                               20% weight/weight NaOH                                                                          55.2     g     precipitation                                solution                                                                      Methanesulphonic acid                                                                           16.15    g                                                  10% weight/weight NaOH                                                                          18.83    ml                                                 solution                                                                      Water             400.8    g     pH = 7.0                                     Ciprofloxacin     50.0     g     preparation by                               Methanesulphonic acid                                                                           16.15    g     precipitation                                L-Arginine        6.113    g                                                  Water             407.33   g     pH = 7.0                                     Ciprofloxacin     50.0     g     preparation by                               Methanesulphonic acid                                                                           16.15    g     precipitation                                Trimethanol (tris)                                                                              4.41     g                                                  Water             408.37   g     pH = 7.0                                     Micronized ciprofloxacin hydrate                                                                5.85     g     Suspension of                                (85.5%)                          micronized                                   Tylopur C 300 P ®                                                                           0.2      g     ciprofloxacin                                Anhydrous glycerol                                                                              2.5      g     hydrate in the                               Water             to 100   ml    aqueous phase                                Micronized ciprofloxacin hydrate                                                                5.85     g     Suspension of                                (85.5%)                          micronized                                   Tylopur C 300 P ®                                                                           0.2      g     ciprofloxacin                                Anhydrous glycerol                                                                              2.5      g     hydrate in the                               Water             to 100   ml    aqueous phase                                Micronized ciprofloxacin hydrate                                                                5.85     g     Suspension of                                (85.5%)                          micronized                                   Tylopur C 300 P ®                                                                           0.75     g     ciprofloxacin                                Tween 80 ®    0.2      g     hydrate in the                               Anhydrous glycerol                                                                              2.5      g     aqueous phase                                Water             to 100   ml    pH 6.8                                       Micronized ciprofloxacin hydrate                                                                5.85     g     Suspension of                                (85.5%)                          micronized                                   Tylopur C 300 P ®                                                                           0.75     g     ciprofloxacin                                Lipoid E 80 ® 0.2      g     hydrate in the                               Anhydrous glycerol                                                                              2.5      g     aqueous phase                                Water             to 1,000 ml    pH 6.8                                       Micronized ciprofloxacin hydrate                                                                5.85     g     Suspension of                                (85.5%)                          micronized                                   Tylopur C 300 P ®                                                                           0.2      g     ciprofloxacin                                Tween 80 ®    0.2      g     hydrate in the                               Anhydrous glycerol                                                                              2.5      g     aqueous phase                                Water             to 100   ml    pH 6.8                                       Micronized ciprofloxacin hydrate                                                                5.85     g     Suspension of                                (85.5%)                          micronized                                   Tylopur C 300 P ®                                                                           0.2      g     ciprofloxacin                                Lipoid E 80 ® 0.2      g     hydrate in the                               Anhydrous glycerol                                                                              2.5      g     aqueous phase                                Water             to 1,000 ml    pH 6.8                                       Ciprofloxacin hydrate                                                                           5.85     g     Suspension of                                (85.5%)                          micronized                                   Tylopur C 300 P ®                                                                           0.2      g     ciprofloxacin                                Lipoid E 80       0.2      g     hydrate in the                                                                aqueous phase                                Water             90.0     ml    pH 7                                         20.                                                                           Ciprofloxacin hydrate                                                                           5.85     g     Suspension of                                (85.5%)                          micronized                                   Tylopur C 300 P ®                                                                           0.2      g     ciprofloxacin                                Citrate buffer    90.0     g     hydrate in the                               solution pH 7                    aqueous phase                                Lipoid E 80       0.2      g     pH 7                                         Ciprofloxacin hydrate                                                                           5.85     g     Suspension of                                (85.5%)                          micronized                                   Tylopur C 300 P ®                                                                           0.2      g     ciprofloxacin                                Phosphate buffer  90.0     g     hydrate in the                               solution pH 7                    aqueous phase                                Lipoid E 80       0.2      ml    pH 7                                         Ciprofloxacin     5.0      g     preparation of                               20% weight/weight NaOH                                                                          3.27     g     precipitation                                solution                                                                      85% strength H.sub.3 PO.sub.4 solution                                                          1.07     g                                                  Tylopur C 300 P ®                                                                           0.2      g                                                  Water             93.14    g                                                  Ciprofloxacin     50.0     g     pH/                                          20% weight/weight NaOH                                                                          55.57    g     osmolality:                                  solution                         285 m osmol/kg                               Citric acid fine grit                                                                           17.9     g                                                  Water             903.6    g                                                  Particle size <10 μm                                                       Precipitation under aseptic conditions via a reaction                         jet 60/40 bar and high pressure homogenization under 400 bar.                 Ciprofloxacin     100.0    g                                                  20% weight/weight NaOH                                                                          62.0     g                                                  solution                                                                      Citric acid fine grit                                                                           19.8     g                                                  Water             869.2    g     pH 7.0                                       Particle size <2-5 μm (90% less than 10 μm)                             Precipitation under aseptic conditions via a reaction                         jet 60/40 bar and high pressure homogenization under 400 bar.                 Ciprofloxacin     100.0    g                                                  20% weight/weight NaOH                                                                          62.0     g                                                  solution                                                                      Citric acid fine grit                                                                           19.8     g                                                  Tween 80 ®    0.1      g                                                  Water             869.2    g     pH 7.0                                       Ciprofloxacin     100.0    g                                                  20% weight/weight NaOH                                                                          62.0     g                                                  solution                                                                      Citric acid fine grit                                                                           19.8     g                                                  Tween 80 ®    1.0      g                                                  Water             868.2    g     pH 7.0                                       Ciprofloxacin     100.0    g                                                  20% weight/weight NaOH                                                                          62.0     g                                                  solution                                                                      Citric acid fine grit                                                                           19.8     g                                                  Tween 80 ®    2.0      g                                                  Water             867.1    g     pH 7.0                                       Ciprofloxacin     100.0    g                                                  20% weight/weight NaOH                                                                          62.0     g                                                  solution                                                                      Citric acid fine grit                                                                           19.8     g                                                  Tween 80 ®    2.0      g                                                  Water             867.1    g     pH 7.0                                       Ciprofloxacin     40.0     g     preparation by                               20% weight/weight NaOH                                                                          24.8     g     precipitation                                solution                                                                      Citric acid fine grit                                                                           7.92     g                                                  Lipoid E 75 ® 4.0      g                                                  Water             343.6    g     pH 7.0                                       30.                                                                           Ciprofloxacin     200.0    g     preparation by                               20% weight/weight NaOH                                                                          62.8     g     precipitation                                solution                                                                      Citric acid fine grit                                                                           41.88    g                                                  Water             738.27   g     pH 7.05                                      Ciprofloxacin     20.0     g     preparation by                               20% weight/weight NaOH                                                                          12.4     g     precipitation                                solution                                                                      15% weight/weight H.sub.3 PO.sub.4                                                              21.38    ml                                                 solution                                                                      Water             to 100   ml    pH 7.05                                      Ciprofloxacin     15.0     g     preparation by                               20% weight/weight NaOH                                                                          9.3      g     precipitation                                solution                                                                      15% weight/weight H.sub.3 PO.sub.4                                                              16.05    ml                                                 solution                                                                      Water             to 100   ml                                                 Ciprofloxacin     25.0     g     preparation by                               20% weight/weight NaOH                                                                          11.25    g     precipitation                                solution                                                                      20% weight/weight lactic acid                                                                   3.72     g                                                  solution                                                                      15% weight/weight H.sub.3 PO.sub.4                                                              21.5     ml                                                 solution                                                                      Water             to 100   ml    pH 7.0                                       Ciprofloxacin     20.0     g     preparation by                               20% weight/weight NaOH                                                                          10.0     g     precipitation                                solution                                                                      20% weight/weight lactic acid                                                                   7.44     g                                                  solution                                                                      15% weight/weight H.sub.3 PO.sub.4                                                              12.0     ml                                                 solution                                                                      Water             to 100   ml    pH 7.0                                       Ciprofloxacin     20.0     g      preparation by                              20% weight/weight NaOH                                                                          8.75     g     precipitation                                solution                                                                      20% weight/weight lactic acid                                                                   11.16    g                                                  solution                                                                      15% weight/weight H.sub.3 PO.sub.4                                                              6.7      ml                                                 solution                                                                      Water             to 100   ml    pH 7.0                                       Ciprofloxacin     20.0     g     preparation by                               20% weight/weight NaOH                                                                          12.4     g     precipitation                                solution                                                                      15% weight/weight H.sub.3 PO.sub.4                                                              21.1     ml                                                 solution                                                                      Tylopur C 300 P ®                                                                           0.05     g                                                  Water             to 100   ml    pH 7.0                                       Ciprofloxacin     20.0     g     preparation by                               20% weight/weight NaOH                                                                          12.4     g     precipitation                                solution                                                                      15% weight/weight H.sub.3 PO.sub.4                                                              21.1     ml                                                 solution                                                                      HPC               0.05     g                                                  Water             to 100   ml    pH 7.0                                       Ciprofloxacin     20.0     g     preparation by                               20% weight/weight NaOH                                                                          12.4     g     precipitation                                solution                                                                      15% weight/weight H.sub.3 PO.sub.4                                                              21.1     ml                                                 solution                                                                      Tween 80 ®    0.05     g                                                  Water             to 100   ml    pH 7.0                                       Ciprofloxacin     20.0     g     preparation by                               20% weight/weight NaOH                                                                          12.4     g     precipitation                                solution                                                                      15% weight/weight H.sub.3 PO.sub.4                                                              21.1     ml                                                 solution                                                                      Tween 80 ®    1.0      g                                                  Water             to 100   ml    pH 7.0                                       40.                                                                           Ciprofloxacin     5        g     Suspension of                                hydrochloride                    ciprofloxacin                                Ethyl oleate      50       g     hydrochloride                                Ciprofloxacin hydrochloride                                                                     10       g                                                  Ethyl oleate      50       g                                                  Ciprofloxacin hydrochloride                                                                     30       g                                                  Ethyl oleate      50       g                                                  Ciprofloxacin hydrochloride                                                                     25       g                                                  Ethyl oleate      50       g                                                  Ciprofloxacin hydrochloride                                                                     5        g                                                  Miglyol 812 ® 50       g                                                  Ciprofloxacin hydrochloride                                                                     10       g                                                  Miglyol 812 ® 50       g                                                  Ciprofloxacin hydrochloride                                                                     15       g                                                  Miglyol 812 ® 50       g                                                  Ciprofloxacin hydrochloride                                                                     5        g                                                  Peanut oil        50       g                                                  Ciprofloxacin hydrochloride                                                                     5        g                                                  Ethyl oleate/Phospholipon                                                                       50       g                                                  100 ® = 99.5/0.5                                                          Ciprofloxacin hydrochloride                                                                     30       g                                                  Ethyl oleate/Phospholipon                                                                       50       g                                                  100 ® = 99.5/0.5                                                          50.                                                                           Ciprofloxacin hydrochloride                                                                     10       g                                                  Miglyol 812 ®/Phospholipon                                                                  50       g                                                  100 ® = 99.5/0.5                                                          Ciprofloxacin hydrochloride                                                                     15       g                                                  Miglyol 812 ®/Phospholipon                                                                  50       g                                                  100 ® = 99.5/0.5                                                          Ciprofloxacin     30       g                                                  Ethyl oleat ® 50       g                                                  Ciprofloxacin     10       g                                                  Miglyol 812 ® 50       g                                                  Ciprofloxacin     2.5      g                                                  Peanut oil        50       g                                                  Ciprofloxacin hydrochloride                                                                     30       g                                                  Ethyl oleate      50       g                                                  Ascorbyl palmitate                                                                              0.1      g                                                  Lecithin (Phospholipon 100) ®                                                               0.5      g                                                  Ciprofloxacin hydrochloride                                                                     25       g                                                  Miglyol 812 ® 50       g                                                  Ascorbyl palmitate                                                                              0.1      g                                                  Lecithin (Phospholipon 100) ®                                                               0.5      g                                                  Ciprofloxacin hydrochloride                                                                     30       g                                                  Ethyl oleate      50       g                                                  Ascorbyl palmitate                                                                              0.1      g                                                  Lecithin (Phospholipon 100) ®                                                               0.5      g                                                  Benzyl alcohol    3        g                                                  Ciprofloxacin hydrochloride                                                                     25       g                                                  Miglyol 812 ® 50       g                                                  Benzyl alcohol    3        g                                                  Lecithin (Phospholipon 100) ®                                                               0.5      g                                                  Ascorbyl palmitate                                                                              0.1      g                                                  Norfloxacin       50       g     preparation by                               20% weight/weight NaOH                                                                          55.2     g     precipitation                                solution                                                                      60.                                                                           Norfloxacin       50       g     preparation by                               20% weight/weight NaOH                                                                          55.2     g     precipitation                                solution                                                                      Citric acid       17.9     g                                                  Tylopur C 300 P  ®                                                                          2.0      g                                                  Water             907.3    g     pH = 6.7                                     Norfloxacin       50       g     preparation by                               20% weight/weight NaOH                                                                          55.2     g     precipitation                                solution                                                                      Citric acid       17.9     g                                                  Tylopur C 300 P ®                                                                           5.0      g                                                  Water             904.3    g     pH = 6.5                                     Ofloxacin         50       g     preparation by                               20% weight/weight NaOH                                                                          55.2     g     precipitation                                solution                                                                      Citric acid       17.9     g                                                  Tylopur C 300 P ®                                                                           7.5      g                                                  Water             901.8    g     pH = 6.5                                     Ofloxacin         50       g     preparation by                               20% weight/weight NaOH                                                                          55.2     g     precipitation                                solution                                                                      Citric acid       17.9     g                                                  Tylopur C 300 P ®                                                                           7.5      g                                                  Water             899.5    g     pH = 6.5                                     Ofloxacin         50       g     preparation by                               20% weight/weight NaOH                                                                          55.2     g     precipitation                                solution                                                                      Citric acid       16.0     g                                                  Tylopur C 300 P ®                                                                           2.0      g                                                  Water             909.2    g     pH = 7.8                                     Ofloxacin         50       g     preparation by                               20% weight/weight NaOH                                                                          55.2     g     precipitation                                solution                                                                      Citric acid       24.7     g                                                  Tylopur C 300 P ®                                                                           2.0      g                                                  Water             900.5    g     pH =  5.3                                    Norfloxacin       50       g     preparation by                               20% weight/weight NaOH                                                                          55.2     g     precipitation                                solution                                                                      Citric acid       17.9     g                                                  Tylopur C 300 P ®                                                                           2.0      g                                                  Tween 20 ®    2.0      g                                                  Water             900.5    g     pH = 6.9                                     Ofloxacin         5.0      g     preparation by                               20% weight/weight NaOH                                                                          9.43     g     precipitation                                solution                                                                      Lipoid E 80 ® 0.2      g                                                  Citric acid       1.8      g                                                  Tylopur C 300 P ®                                                                           0.2      g                                                  Water             77.17    g                                                  Pefloxacin        50.0     g     preparation by                               Methanesulphonic acid                                                                           16.15    g     precipitation                                10% weight/weight NaOH                                                                          10.83    ml                                                 solution                                                                      Water             400.8    g     pH = 7.0                                     Norfloxacin       50.0     g     preparation by                               Methanesulphonic acid                                                                           16.15    g     precipitation                                L-Arginine        6.11     g                                                  Water             407.33   g                                                  70.                                                                           Norfloxacin       50.0     g     preparation by                               Methanesulphonic acid                                                                           16.15    g     precipitation                                Trimethanol (tris)                                                                              4.41     g                                                  Water             408.3    g     pH = 7.0                                     Micronized norfloxacin hydrate                                                                  5.85     g     Suspension of                                (85.5%)                          micronized                                   Tylopur C 300 P ®                                                                           0.2      g     norfloxacin                                  Anhydrous glycerol                                                                              2.5      g     hydrate in the                               Water             to 100   ml    aqueous phase                                Micronized ofloxacin hydrate                                                                    5.85     g     Suspension of                                (85.5%)                          micronized                                   Tylopur C 300 P ®                                                                           0.75     g     norfloxacin                                  Anhydrous glycerol                                                                              2.5      g     hydrate in the                               Water             to 100   ml    aqueous phase                                Micronized amifloxacin hydrate                                                                  5.85     g     Suspension of                                (85.5%)                          micronized                                   Tylopur C 300 P ®                                                                           0.75     g     norfloxacin                                  Tween 80 ®    0.2      g     hydrate in the                               Anhydrous glycerol                                                                              2.5      g     aqueous phase                                Water             to 100   ml    pH 6.8                                       Micronized pefloxacin hydrate                                                                   5.85     g     Suspension of                                (85.5%)                          micronized                                   Tylopur C 300 P ®                                                                           0.75     g     norfloxacin                                  Lipoid E 80 ® 0.2      g     hydrate in the                               Anhydrous glycerol                                                                              2.5      g     aqueous phase                                Water             to 100   ml    pH 6.8                                       Micronized enrofloxacin hydrate                                                                 5.85     g     Suspension of                                (85.5%)                          micronized                                   Tylopur C 300 P ®                                                                           0.2      g     enrofloxacin                                 Tween 80 ®    0.2      g     hydrate in the                               Anhydrous glycerol                                                                              2.5      g     aqueous phase                                Water             to 100   ml    pH 6.8                                       Micronized enrofloxacin hydrate                                                                 5.85     g     Suspension of                                (85.5%)                          micronized                                   Tylopur C 300 P ®                                                                           0.2      g     enrofloxacin                                 Lipoid 80 ®   0.2      g     hydrate in the                               Anhydrous glycerol                                                                              2.5      g     aqueous phase                                Water             to 100   ml    pH 6.8                                       Enrofloxacin hydrate                                                                            5.85     g     Suspension of                                (85.5%)                          micronized                                   Tylopur C 300 P ®                                                                           0.2      g     enrofloxacin                                 Lipoid E 80 ® 0.2      g     hydrate in the                                                                aqueous phase                                Water             90.0     ml    pH 7                                         Enrofloxacin hydrate                                                                            5.85     g     Suspension of                                (85.5%)                          micronized                                   Tylopur C 300 P ®                                                                           0.2      g     enrofloxacin                                 Citrate buffer solution pH 7                                                                    90.0     g     hydrate in the                                                                aqueous phase                                Lipoid E 80 ® 0.2      g     pH 7                                         Enrofloxacin hydrate                                                                            5.85     g     Suspension of                                (85.5%)                          micronized                                   Tylopur C 300 P ®                                                                           0.2      g     enrofloxacin                                 Phosphate buffer solution pH 7                                                                  90.0     g     hydrate in the                                                                aqueous phase                                Lipoid E 80 ® 0.2      ml    pH 7                                         80.                                                                           Active compound A 5.0      g     preparation by                               20% weight/weight NaOH                                                                          2.27     g     precipitation                                solution                                                                      85% H.sub.3 PO solution                                                                         1.07     g                                                  Tylopur C 300 P ®                                                                           0.2      g                                                  Water             93.14    g                                                  Active compound B 50.0     g     pH 7                                         20% weight/weight NaOH                                                                          55.5     g     pH 7                                         solution                         osmolality:                                                                   285 m osmol/kg                               Citric acid fine grit                                                                           17.9     g                                                  Water             903.6    g                                                  Particle size <10 μm                                                       Precipitation under aseptic conditions via a reaction                         jet 60/40 bar and high pressure homogenization under 400 bar.                 Active compound C 100.0    g                                                  20% weight/weight NaOH                                                                          62.0     g                                                  solution                                                                      Citric acid fine grit                                                                           19.8     g                                                  Water             869.2    g                                                  Particle size     2-5      lm    (90% under                                                                    10 μm)                                    Precipitation under aseptic conditions via a reaction                         jet 60/40 bar and high pressure homogenization under 400 bar.                 Active compound A 100.0    g                                                  20% weight/weight NaOH                                                                          62.0     g                                                  solution                                                                      Citric acid fine grit                                                                           19.8     g                                                  Tween 80 ®    0.1      g                                                  Water             869.2    g     pH 7.0                                       Active compound B 100.0    g                                                  20% weight/weight NaOH                                                                          62.0     g                                                  solution                                                                      Citric acid fine grit                                                                           19.8     g                                                  Tween 80 ®    1.0      g                                                  Water             868.2    g     pH 7.0                                       Active compound B 100.0    g                                                  20% weight/weight NaOH                                                                          62.0     g                                                  solution                                                                      Citric acid fine grit                                                                           19.8     g                                                  Tween 80 ®    2.0      g                                                  Water             867.1    g     pH 7.0                                       Active compound A 100.0    g                                                  20% weight/weight NaOH                                                                          62.0     g                                                  solution                                                                      Citric acid fine grit                                                                           19.8     g                                                  Tween 80 ®    2.0      g                                                  Water             867.1    g     pH 7.0                                       Active compound B 40.0     g     preparation by                               20% weight/weight NaOH                                                                          24.8     g     precipitation                                solution                                                                      Citric acid fine grit                                                                           7.92     g                                                  Lipoid E 75 ® 4.0      g                                                  Water             343.6    g     pH 7.0                                       Active compound B 200.0    g     preparation by                               20% weight/weight NaOH                                                                          62.8     g     precipitation                                solution                                                                      Citric acid fine grit                                                                           41.88    g                                                  Water             738.27   g     pH 7.05                                      Active compound C 20.0     g     preparation by                               20% weight/weight NaOH                                                                          12.4     g     precipitation                                solution                                                                      15% weight/weight H.sub.3 PO                                                                    21.38    ml                                                 solution                                                                      Water             to 100   ml    pH 7.05                                      90.                                                                           Active compound B 15.0     g     preparation by                               20% weight/weight NaOH                                                                          12.4     g     precipitation                                solution                                                                      15% weight/weight H.sub.3 PO                                                                    16.05    ml                                                 solution                                                                      Water             to 100   ml                                                 Active compound A 20.0     g     preparation by                               20% weight/weight NaOH                                                                          11.25    g     precipitation                                solution                                                                      20% weight/weight lactic acid                                                                   3.72     g                                                  solution                                                                      15% weight/weight H.sub.3 PO.sub.4                                                              21.5     ml                                                 solution                                                                      Water             to 100   ml    pH 7.0                                       Active compound B 20.0     g     preparation by                               20% weight/weight NaOH                                                                          10.0     g     precipitation                                solution                                                                      20% weight/weight lactic acid                                                                   7.44     g                                                  solution                                                                      15% weight/weight H.sub.3 PO.sub.4                                                              12.0     ml                                                 solution                                                                      Water             to 100   ml    pH 7.0                                       Active compound B 20.0     g     preparation by                               20% weight/weight NaOH                                                                          8.75     g     precipitation                                solution                                                                      20% weight/weight lactic acid                                                                   11.16    g                                                  solution                                                                      15% weight/weight H.sub.3 PO.sub.4                                                              6.7      ml                                                 solution                                                                      Water             to 100   ml    pH 7.0                                       Active compound C 20.0     g     preparation by                               20% weight/weight NaOH                                                                          12.4     g     precipitation                                solution                                                                      20% weight/weight lactic acid                                                                   21.1     ml                                                 solution                                                                      Tylopur C 300 P ®                                                                           0.05     g                                                  Water             to 100   ml    pH 7.0                                       Active compound C 20.0     g     preparation by                               20% weight/weight NaOH                                                                          12.4     g     precipitation                                solution                                                                      15% weight/weight H.sub.3 PO.sub.4                                                              21.1     ml                                                 solution                                                                      HPC               0.05     g                                                  Water             to 100   ml    pH 7.0                                       Active compound B 20       g     preparation by                               20% weight/weight NaOH                                                                          12.4     g     precipitation                                solution                                                                      15% weight/weight H.sub.3 PO.sub.4                                                              21.1     ml                                                 solution                                                                      Tween 80 ®    0.05     g                                                  Water             to 100   ml    pH 7.0                                       Active compound C 20.0     g     preparation by                               20% weight/weight NaOH                                                                          12.4     g     precipitation                                solution                                                                      15% weight/weight H.sub.3 PO.sub.4                                                              21.1     ml                                                 solution                                                                      Tween 80 ®    1.0      g                                                  Water             to 100   ml    pH 7.0                                       Norfloxacin       5        g     suspension of                                                                 norfloxacin in                                                                oily excipient                               Ofloxacin         10       g                                                  Ethyl oleate      50       g                                                  100.                                                                          Norfloxacin       30       g                                                  Ethyl oleate      50       g                                                  101.                                                                          Norfloxacin       25       g                                                  Ethyl oleate      50       g                                                  102.                                                                          Ofloxacin         5        g                                                  Miglyol 812 ® 50       g                                                  103.                                                                          Pefloxacin        10       g                                                  Miglyol 812 ® 50       g                                                  104.                                                                          Active compound A 15       g                                                  Miglyol 812 ® 50       g                                                  105.                                                                          Active compound   5        g                                                  Peanut oil        50       g                                                  106.                                                                          Active compound B 5        g                                                  Ethyl oleate/phospholipon                                                                       50       g                                                  100 ® = 99.5/0.5                                                          107.                                                                          Active compound C 30       g                                                  Ethyl oleate/phospholipon                                                                       50       g                                                  100 ® = 99.5/0.5                                                          108.                                                                          Active compound B 10       g                                                  Miglyol 812 ®/phospholipon                                                                  50       g                                                  100 ® = 99.5/0.5                                                          109.                                                                          Active compound A 15       g                                                  Miglyol 812 ®/phospholipon                                                                  50       g                                                  100 ® = 99.5/0.5                                                          110.                                                                          Active compound C 30       g                                                  Ethyl oleate      50       g                                                  111.                                                                          Active compound A 10       g                                                  Miglyol 812 ® 50       g                                                  112.                                                                          Active compound B 2.5      g                                                  Peanut oil        50       g                                                  113.                                                                          Active compound B 30       g                                                  Ethyl oleate      50       g                                                  Ascorbyl palmitate                                                                              0.1      g                                                  Lecithin (Phospholipon 100 ®)                                                               0.5      g                                                  114.                                                                          Active compound C 25       g                                                  Miglyol 812 ® 50       g                                                  Ascorbyl palmitate                                                                              0.1      g                                                  Lecithin (Phospholipon 100 ®)                                                               0.5      g                                                  115.                                                                          Active compound B 30       g                                                  Ethyl oleate      50       g                                                  Ascorbyl palmitate                                                                              0.1      g                                                  Lecithin (Phospholipon 100 ®)                                                               0.5      g                                                  Benzyl alcohol    3        g                                                  116.                                                                          Active compound C 25       g                                                  Miglyol 812 ® 50       g                                                  Benzyl alcohol    3        g                                                  Lecithin (Phospholipon 100 ®)                                                               0.5      g                                                  Ascorbyl palmitate                                                                              0.1      g                                                  117.                                                                          Ciprofloxacin hydrochloride                                                                     5.8      g                                                  Benzyl alcohol    2.0      g                                                  Soy bean lecithin purified                                                                      0.5      g                                                  Medium chain triglycerides                                                                      ad 100.0 ml                                                 DAB9                                                                          118.                                                                          Ciprofloxacin hydrochloride                                                                     11.6     g                                                  Benzyl alcohol    2.0      g                                                  Egg lecithin purified                                                                           0.5      g                                                  Medium chain triglycerides                                                                      ad 100.0 ml                                                 DAB9                                                                          119.                                                                          Ciprofloxacin hydrochloride                                                                     11.6     g                                                  Benzyl alcohol    2.0      g                                                  Soy bean lecithin purified                                                                      5.0      g                                                  Miglyol 812 ® ad 100.0 ml                                                 120.                                                                          Ciprofloxacin hydrochloride                                                                     11.6     g                                                  Ethanol absolute  5.0      g                                                  Egg lecithin purified                                                                           5.0      g                                                  Medium chain triglycerides                                                                      ad 100.0 ml                                                 DAB9                                                                          121.                                                                          Ciprofloxacin hydrochloride                                                                     11.6     g                                                  Ethanol absolute  5.0      g                                                  Soy bean lecithin purified                                                                      5.0      g                                                  Lactic acid concentrated                                                                        0.05-1.0 g                                                  Miglyol 812 ® ad 100   ml                                                 122.                                                                          Ciprofloxacin lactate                                                                           12.7     g                                                  Benzyl alcohol    2.0      g                                                  Soy bean lecithin purified                                                                      5.0      g                                                  Medium chain triglycerides                                                                      ad 100.0 ml                                                 123.                                                                          Ciprofloxacin mesilate                                                                          13.42    g                                                  Ethanol           10.0     g                                                  Egg lecithin purified                                                                           10.0     g                                                  Ethyl oleate      ad 100.0 ml                                                 124.                                                                          Ciprofloxacin lactate                                                                           12.7     g                                                  Ethanol           5.0      g                                                  Soy bean lecithin purified                                                                      5.0      g                                                  Lactic acid concentrate                                                                         0.05-1.0 g                                                  Miglyol 812 ® ad 100.0 ml                                                 125.                                                                          Ciprofloxacin hydrochloride                                                                     11.6     g                                                  Ethanol           10.0     g                                                  Soy bean lecithin purified                                                                      5.0      g                                                  Methane sulphonic acid                                                                          0.05-1.0 g                                                  Miglyol 812 ® ad 100.0 ml                                                 126.                                                                          Ciprofloxacin hydrochloride                                                                     11.6     g                                                  Ethanol           5.0      g                                                  Soy bean lecithin purified                                                                      5.0      g                                                  Citric acid anhydrous micronized                                                                0.05-2.0 g                                                  Miglyol 812 ® ad 100.0 ml                                                 ______________________________________                                    

It will be appreciated that the instant specification and claims are setforth by way of illustration and not limitation, and that variousmodifications and changes may be made without departing from the spiritand scope of the present invention.

What is claimed is:
 1. An intramuscular injection formulation of agyrase inhibitor comprising about 0.05 to 70% by weight of a gyraseinhibitor of the formula ##STR5## in which R¹ stands for methyl, ethyl,propyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl,methoxy, amino, methylamino, dimethylamino, ethylamino, phenyl,4-fluorophenyl or 2,4-difluorophenyl,R² stands for hydrogen, alkylhaving 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl,R³ stands for methyl or a cyclic amino group of the formula ##STR6##wherein R⁴ stands for hydrogen, alkyl having 1 to 4 carbon atoms,2-hydroxyethyl, allyl, propargyl, 2-oxopropyl, 3-oxobutyl, phenacyl,formyl, CFCl₂ -S-, CFCl₂ -SO₂ -, CH₃ O-CO-S-, benzyl, 4-aminobenzyl or##STR7## R⁵ stands for hydrogen or methyl, R⁶ stands for hydrogen, alkylhaving 1 to 4 carbon atoms, phenyl or benzyloxymethyl, R⁷ stands forhydrogen, amino, methylamino, ethylamino, aminomethyl,methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, hydroxyl orhydroxymethyl and R⁸ stands for hydrogen, methyl, ethyl or chlorine, Xstands for fluorine, chlorine or nitro and A stands for N orC-R⁶,wherein R⁶ stands for hydrogen, halogen, methyl or nitro or,together with R¹, forms a bridge having the structure ##STR8## or a saltthereof with an acid or base in oily suspension.
 2. An intramuscularinjection formulation according to claim 1, wherein the particle size ofthe gyrase inhibitor is about 0.05-150 μm.
 3. An intramuscular injectionformulation according to claim 1, wherein the particle size of thegyrase inhibitor is about 4 to 40 μm.
 4. An intramuscular injectionformulation according to claim 1, containing about 2.5 to 50% by weightof the gyrase inhibitor.
 5. A process for the preparation of anintramuscular injection formulation according to claim 1, comprisingincorporating an active compound of the formula I, optionally whilegassing with nitrogen, into an oil which is initially introduced intothe vessel and optionally already contains an antioxidant, stabilizer orsurface-active substance, and optionally after-homogenizing the oil. 6.In the treatment of a patient with a gyrase inhibitor, the improvementwhich comprises administering said gyrase inhibitor intramuscularly inthe form of a formulation according to claim
 1. 7. An intramuscularinjection formulation according to claim 1, comprising an oilysuspension and containing the active compound in water-soluble,crystalline or amorphous form as the hydrochloride, lactate, mesylate,p-tolyl sulphonate or salt of another physiologically well-toleratedacid.
 8. An intramuscular injection formulation according to claim 1,comprising an oily suspension and containing a well-tolerated tensideselected from the group consisting of soy bean lecithin, egg lecithin,brain lecithin or rape lecithin in a concentration of about 0.1 to 30%W/V.
 9. An intramuscular injection formulation according to claim 1,comprising an oily suspension and containing a well-tolerated tensideselected from the group consisting of soy bean lecithin, egg lecithin,brain lecithin or rape lecithin in a concentration of about 0.2 to 10TW/V.
 10. An intramuscular injection formulation according to claim 1,comprising an oily suspension and containing a well-tolerated tensideselected from the group consisting of soy bean lecithin, egg lecithin,brain lecithin or rape lecithin in a concentration of about 0.5 to 5%W/V.
 11. An intramuscular injection formulation according to claim 7,containing 1 to 300 mmol/1 of physiologically well-tolerated acid inexcess of the amount required to form the salt.
 12. An intramuscularinjection formulation according to claim 7, containing 5 to 50 mmol/1 ofphysiologically well-tolerated acid in excess of the amount required toform the salt.
 13. An intramuscular injection formulation according toclaim 7, containing 10 to 30 mmol/1 of physiologically well-toleratedacid in excess of the amount required to form the salt.
 14. Anintramuscular injection formulation according to claim 11, wherein theacid is lactic acid or citric acid.
 15. An intramuscular injectionformulation according to claim 1, wherein the gyrase inhibitor isenrofloxacin.